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Integrated multi-omics analysis of RB-loss identifies widespread cellular programming and synthetic weaknesses

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Item Type:Article
Title:Integrated multi-omics analysis of RB-loss identifies widespread cellular programming and synthetic weaknesses
Creators Name:Rajasekaran, S. and Siddiqui, J. and Rakijas, J. and Nicolay, B. and Lin, C. and Khan, E. and Patel, R. and Morris, R. and Wyler, E. and Boukhali, M. and Balasubramanyam, J. and Ranjith Kumar, R. and Van Rechem, C. and Vogel, C. and Elchuri, S.V. and Landthaler, M. and Obermayer, B. and Haas, W. and Dyson, N. and Miles, W.
Abstract:Inactivation of RB is one of the hallmarks of cancer, however gaps remain in our understanding of how RB-loss changes human cells. Here we show that pRB-depletion results in cellular reprogramming, we quantitatively measured how RB-depletion altered the transcriptional, proteomic and metabolic output of non-tumorigenic RPE1 human cells. These profiles identified widespread changes in metabolic and cell stress response factors previously linked to E2F function. In addition, we find a number of additional pathways that are sensitive to RB-depletion that are not E2F-regulated that may represent compensatory mechanisms to support the growth of RB-depleted cells. To determine whether these molecular changes are also present in RB1(−/−) tumors, we compared these results to Retinoblastoma and Small Cell Lung Cancer data, and identified widespread conservation of alterations found in RPE1 cells. To define which of these changes contribute to the growth of cells with de-regulated E2F activity, we assayed how inhibiting or depleting these proteins affected the growth of RB1(−/−) cells and of Drosophila E2f1-RNAi models in vivo. From this analysis, we identify key metabolic pathways that are essential for the growth of pRB-deleted human cells.
Keywords:Retinal Neoplasms, Retinoblastoma, Retinoblastoma Binding Proteins, Tumor Cell Line, Ubiquitin-Protein Ligases, Animals, Mice
Source:Communications Biology
Publisher:Springer Nature
Page Range:977
Date:17 August 2021
Additional Information:Erratum in: Commun Biol 4(1): 1156.
Official Publication:https://doi.org/10.1038/s42003-021-02495-2
PubMed:View item in PubMed

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